994 Kotalwar et al.
Asian J. Chem.
+
1
glycerol has been received as greener medium for various
organic transformations [21-24]. Radatz et al. [25] reported
glycerol as recyclable solvent for synthesis of benzodiazepines
and benzimidazoles. The unique physico-chemical nature
of glycerol such as non-toxicity, biodegradability, polarity,
recyclability, high boiling point, lower vapour pressure and
ready availability from renewable feed stocks makes it an ideal
reaction medium.
In recent year, considerable attention has been attracted
towards the application of microwave irradiation to organic
synthesis. Under microwave irradiation conditions, organic
reactions can be accelerated and selectivity’s of the ensuing
products can be obtained by choosing appropriate microwave
parameters, thus offering several advantages over conventional
heating, such as instantaneous and rapid heating (deep inside
heating), high temperature homogeneity and selective heating
Intensity): 316 (M , 100). H NMR (DMSO-d
6
) δ: 3.07 (t, 1H),
3.32 (dd, 1H), 4.99 (dd, 1H), 7.12-8.05 (m, 14H, Ar-H).
RESULTS AND DISCUSSION
In the present work, firstly we optimized cycloconden-
sation of prop-2-en-1-ones with 2-aminothiophenol in various
solvent such as EtOH, DMF, toluene and water but we have
not get satisfactory result in reaction time and yield of products
whereas DMF and toluene are high boiling solvent and not
recommendable from an environmental perspective. Ethanol
gave good result as compare to DMF, toluene and water after
long reaction time 7 h. When we carried reaction using glycerol
gave better result as compared other solvent (Table-1: entry
1-5). In PEG-400 the reaction completed within 4 h with 78 %
yield. Further, same reaction in glycerol was performed using
a microwave irradiation, the reaction completed within 3-5
min with 78 % yield. Glycerol attributes more polar a reaction
mixture, has greater ability to couple with the microwave
energy and accelerate the rate of reaction comparing with
conventional heating (Table-2: entry 6). The high viscosity of
glycerol might be a disadvantage, yet increasing the tempe-
rature above 50 °C decreases their viscosity. Glycerol has three
hydroxyl groups that are responsible for its solubility in water
and has a higher boiling point, lower vapour pressure as com-
pared with water, make it easy to isolate the reaction product
by simple extraction. The key intermediates, chalcones (1)
required for the synthesis were synthesized following literature
procedure [41]. Compounds (3a-h) were prepared by the reac-
tion of compound (1) with o-aminothiophenol (2) in presence
of acetic acid in glycerol at 120 °C. under microwave irradia-
tion with better yields. The reaction sequence is outlined in
Scheme-I.
[
26-28]. Since the first reports in 1986 [29,30] the use of the
microwave heating technique has become an essential tool in
all areas of synthetic chemistry, including solvent-free and
water-mediated reactions [31-35]. Cabrera et al. [36] reported
that the glycerol has proved to be an efficient solvent for the
oxidation of aromatic, aliphatic and functionalized thiols under
microwave irradiation.
Keeping in view as part of our interest in developing
greener and efficient synthetic routes for biologically relevant
compounds [37-40], herein we have synthesized 2,3-dihydro-
1-5-benzothiazepines by employing glycerol under microwave
irradiation.
EXPERIMENTAL
Chemicals and solvents required were obtained from
1
Merck, Spectorchem and S.D. Fine. H NMR spectra were
recorded at 300 MHz on Bruker DRX-300. The mass spectra
were recorded on JEOL-Accu TOF DART-MS-T 100Lc. The
melting points were taken in open capillary and are uncorrected.
TABLE-1
OPTIMIZATION OF SOLVENT EFFECT
ON THE MODEL REACTION
c
General procedure for the synthesis of 1,5-benzothiazepines
(
3a-h)
Conventional synthetic route: A mixture of prop-2-en-
-ones (0.002 mol) and o-aminothiophenol (0.0022 mol) was
Reaction
conditions
Reflux
Reflux
Reflux
Reflux
Warm
MW (100
W120 °C)
a
Temp.
(°C)
Yield
(%)
Entry
Solvent
Time (h)
1
2
3
4
5
6
Ethanol
DMF
Toluene
Water
Glycerol
Glycerol
7
6
6
8
4
78
73
68
62
20
78
78
1
153
111
100
120
120
dissolved in glycerol (10 mL). Catalytic amount of glacial
acetic acid was added to the solution and it was then warm on
an oil bath at 120 °C for 4 h. The progress of the reaction was
monitored on TLC plate using hexane: ethyl acetate. After
completion, the reaction mass was poured in ice cold water
and extracted with EtOAc. The solvent was removed and crude
product was crystallized using proper solvents.
b
3-5 min
a
Reaction of chalcone with o-aminothiophenol in presence of acetic
acid under conventional heating; Reaction of chalcone with o-
aminothiophenol in presence of acetic acid under microwave
irradiation for 3-6 min; Isolated yields.
b
c
Microwave irradiation synthetic route (3a-h): In a coni-
cal flask, prop-2-en-1-ones (0.002 mol), o-aminothiophenol
(
0.0022 mol) and catalytic amount of glacial acetic acid was
Conclusion
dissolved in glycerol. The reaction mixture was irradiated using
microwave at 100 Watt for 3.5 min. The progress of the reaction
was monitored on TLC plate. After completion, the reaction
mixture was poured in ice cold water and was extracted with
EtOAc. The solvent was removed and crude product was crysta-
llized using proper solvents.
In conclusion, glycerol has proved an efficient solvent for
the synthesis of 1,5-benzothiazipines under microwave irradia-
tion. In the present study proposed method has advantage over
existing conventional method with high yield and shorter
reaction time with good to excellent yields. In addition glycerol,
which is non-toxic, biodegradable and recyclable liquid manu-
factured from renewable sources.
Characteristic absorption of 2a as one of the representative
+
product (2a-h) has been presented bellow MS ESI (m/z, %